HSV can cause a variety of ocular diseases in humans ranging in severity from mild to sight- threatening. In addition, HSV causes cold sores, genital sores, and encephalitis. The lifecycle of HSV comprises an acute infection at mucosal sites such as the cornea during which all virus genes are expressed, and latency in neurons, during which gene expression is limited. Latency is a major hurdle for treatment of herpetic diseases, the majority of which result from reactivation from latency. The NEI's 2012 Strategic Plan therefore seeks to elucidate immunity to HSV during acute and latent infection. The over-arching goal of this project, now in its 20th year, is to study innate and adaptive immunity to HSV during all stages of pathogenesis. Three specific aims are proposed. We will examine aspects of innate (IFN-driven) and adaptive (T cell- driven) immunity, in addition to xenophagy - an aspect of the autophagy pathway that is emerging as an important link between innate and adaptive immunity. We will examine the roles of these defense pathways, in conjunction with the HSV genes that counter them, in acute infection of the cornea and nervous system, and in latency and reactivation. Much of the work will be performed using an in vivo mouse corneal model, although some aspects will utilize a new in vitro system. The following hypotheses will be tested: The balance of IFN-driven innate immunity, and viral genes that dampen the IFN response determines the outcome of HSV corneal infection. Innate immunity is critical for protection of the cornea from infection. This aim will further dissect the factors are important in recognition of the invading pathogen and generating an appropriate immune response. We will also study the impact of viral countering of the host response. HSV genes that thwart the host autophagy response also modulate the development of T cell immunity, thereby affecting HSV replication and pathogenesis. By controlling the autophagy/xenophagy response, we, and others have shown that HSV controls both direct intracellular degradation, and antigen presentation. Through creation and use of HSV recombinants altered in ability to modulate autophagy, in combination with mice lacking autophagy in their antigen presenting cells, we will determine the impact of host xenophagy on development of T cell immunity, pathogenesis, and immunopathology following HSV infection. Autophagy and innate immunity are critical host responses that promote the establishment and maintenance of HSV latency. We have shown that autophagy/xenophagy is especially important for protection of neurons from acute virus infection. We will use a new in vitro HSV latency model of adult sensory neurons to examine the role of xenophagy in the establishment and maintenance of latency. This proposal will thereby examine the host-pathogen interface not only through study of the roles of host defense against HSV, but also through study of how HSV counters host immunity. If successful, these aims will bring an improved understanding of host and viral factors involved in HSV pathogenesis.